Treatment Options for Patients With Localized, Metastatic Melanoma

Treatment Options for Patients With Localized, Metastatic Melanoma

There are a growing number of treatment options, from surgery and radiation to immunotherapy and targeted therapy, for melanoma. Although patients have benefited from the expansion of options, questions have arisen about how to select optimal treatment, such as whether to recommend lymph node dissection or immunotherapy compared with targeted therapy.

The June 2 session “Clinical Problems in the Immunotherapy, Surgery, and Radiation Therapy of Melanoma” included a case study in which a patient with melanoma experienced progression from localized to metastatic disease, and the treatment selection from the perspectives of a surgical, radiation, and medical oncologist.

Dr. Vernon K. Sondak speaks during the session “Clinical Problems in the Immunotherapy, Surgery, and Radiation Therapy of Melanoma.”

Vernon K. Sondak, MD, of the Moffitt Cancer Center, opened the session by describing a 43-year-old woman with newly diagnosed melanoma in her left buttock. The patient had surgery to remove the melanoma, and three left inguinal sentinel lymph nodes were biopsied. Because two of the three lymph nodes were positive for melanoma and there was no evidence of brain metastasis by MRI, the patient was determined to have stage IIIC T3b/T4a based on the American Joint Commission on Cancer (AJCC) eighth edition criteria.

The oncology team had to make a treatment decision, which Dr. Sondak posed to the audience: to observe the patient without further treatment, perform complete lymph node dissection (CLND), prescribe a standard therapy—ipilimumab or interferon alfa (IFN-α)—or enroll the patient in a clinical trial of a next-generation anti–PD-1 inhibitor or targeted therapy.

Complete Lymph Node Dissection

Several arguments can be made for performing radical lymphadenectomy for this type of patient, such as reducing the risk of regional recurrence, providing more staging information for clinical decision making, and determining eligibility for clinical trials.

“What people really want to know is, will this additional surgery now—compared to perhaps waiting for a recurrence—improve survival?” Dr. Sondak said. The DeCOG-SLT trial, a small phase III trial of 483 patients with melanoma, found no difference in 3-year overall survival (OS) among patients who were randomly selected to have CLND compared with observation. The larger MSLT-II trial, which will be published June 8, will provide more information about 3-year OS, but, as Dr. Sondak noted, “3 years is not enough to tell the whole story.”

Even after the MSLT-II data are available, it will still be a challenge to determine which patients could benefit from CLND. “First and foremost, therapeutic lymph node dissection is appropriate for any patient with clinically detectable lymph node metastases,” Dr. Sondak said. However, nodal observation instead of CLND may be appropriate for certain patients who have a thin and nonulcerated primary tumor and only one positive sentinel lymph node, who want to avoid lymphedema, do not want to participate in a clinical trial, and agree to comply with careful surveillance.

The case study patient declined CLND out of fear of developing lymphedema that would make it difficult to work. After 7 months, the patient returned with palpable lymph nodes in her left groin and underwent a CLND, which found five positive inguinal lymph nodes. Her oncology team had to decide whether to treat her disease with postoperative radiation, standard therapy, immunotherapy, or targeted therapy.

Adjuvant Radiation Therapy

The phase III ANZMTG 01.02/TROG 02.01 trial of 123 patients with melanoma who had lymphadenectomy offers some guidance about the role of adjuvant radiation therapy. During a 6-year follow-up, patients in the trial who were randomly selected to receive radiation had lower rates of lymph node–field relapse compared with the observation group, but did not have lower rates of distant relapse or higher rates of relapse-free survival or OS. The patients who received radiation also had higher rates of lymphedema.

Dr. Amit Maity speaks during the session “Clinical Problems in the Immunotherapy, Surgery, and Radiation Therapy of Melanoma.”

“There’s not a very clear and absolute recommendation that you should use radiation. I think you can argue either way, and should have a discussion with the patient to tell them the pros and cons,” said Amit Maity, MD, PhD, of the University of Pennsylvania. Dr. Maity outlined the National Comprehensive Cancer Network recommendations for adjuvant radiation therapy, which were based on the results of the ANZMTG 01.02/TROG 02.01 trial.

Dr. Georgina V. Long speaks during the session “Clinical Problems in the Immunotherapy, Surgery, and Radiation Therapy of Melanoma.”

Immunotherapy and Targeted Therapy

Neither of the two standard therapies, high-dose ipilimumab and IFN-α, were appropriate for the case study patient, said Georgina V. Long, BSc, PhD, MBBS, FRACP, of the University of Sydney, Australia. High-dose ipilimumab is often associated with severe toxicity and IFN-α appears to offer minimal benefit to patients with large relapsed lymph nodes, she explained. Instead, oncologists at her institution generally discuss clinical trial options with this type of patient.

The case study patient received radiation therapy and also participated in a clinical trial in which she was randomly assigned to receive IFN-α. After 1 year of treatment, however, the patient developed lung and lymph node metastases, and was determined to have stage IV M1b(1) disease according to the AJCC eighth edition criteria.

An important consideration for this patient was whether she had a mutation in the BRAF gene, which is present in about 40% of patients with advanced melanoma. “Every patient who is about to embark on systemic therapy should have their BRAF mutation status determined,” ideally by DNA sequencing and not just immunohistochemistry, Dr. Long said.

The patient did not have the V600E or V600K mutation required for eligibility for a BRAF inhibitor (dabrafenib or vemurafenib) or MEK inhibitor (trametinib or cobimetinib). Dr. Long said that studies have demonstrated that patients receiving BRAF and MEK inhibitors have better long-term OS than those taking ipilimumab and PD-1 inhibitors.

It can be a difficult clinical decision, as with the case study patient, whether to use anti–PD-1 therapy alone (pembrolizumab or nivolumab), which is well-tolerated, or anti–PD-1 therapy in combination with ipilimumab, which has high rates of grade 3 or 4 adverse events and treatment discontinuation. Data presented at the American Association of Cancer Research Annual Meeting this year provided some hints. Nivolumab plus ipilimumab was associated with better OS than nivolumab alone, although the difference did not emerge until after 12 months of treatment and was not significant. Data from 3- and 5-year follow-up studies are necessary to make an assessment, Dr. Long said

For now, three subgroups of patients appear most likely to experience an OS benefit from anti–PD-1 and ipilimumab combination therapy compared with anti–PD-1 monotherapy: patients with a BRAF mutation, low PD-L1 tumor expression, or high levels of lactate dehydrogenase. Combination therapy also appears to confer faster response than monotherapy, which could be important for patients with rapidly progressing disease.